Title | Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Gerke TA, Martin NE, Ding Z, Nuttall EJ, Stack EC, Giovannucci E, Lis RT, Stampfer MJ, Kantoff PW, Parmigiani G, Loda M, Mucci LA |
Journal | Prostate |
Volume | 75 |
Issue | 16 |
Pagination | 1926-33 |
Date Published | 2015 Dec |
ISSN | 1097-0045 |
Keywords | Aged, Aged, 80 and over, Area Under Curve, Biomarkers, Tumor, Cyclin D1, Disease Progression, Follow-Up Studies, Gene Expression Profiling, Humans, Male, Middle Aged, Neoplasm Invasiveness, Osteopontin, Prognosis, Prostate, Prostatic Neoplasms, PTEN Phosphohydrolase, Smad4 Protein |
Abstract | BACKGROUND: We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer. METHODS: Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; nā=ā276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; nā=ā347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays. RESULTS: During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up. CONCLUSIONS: Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research. |
DOI | 10.1002/pros.23090 |
Alternate Journal | Prostate |
PubMed ID | 26469352 |
PubMed Central ID | PMC4831584 |
Grant List | P50 CA090381 / CA / NCI NIH HHS / United States UM1CA16755201 / CA / NCI NIH HHS / United States R01CA133891 / CA / NCI NIH HHS / United States R01CA141298 / CA / NCI NIH HHS / United States P50CA090381 / CA / NCI NIH HHS / United States R01CA136578 / CA / NCI NIH HHS / United States R01 CA133891 / CA / NCI NIH HHS / United States T32 CA009001 / CA / NCI NIH HHS / United States UM1 CA167552 / CA / NCI NIH HHS / United States R01 CA136578 / CA / NCI NIH HHS / United States R01 CA141298 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.